Gap junctions are involved in intercellular communication, which is important for maintaining tissue and organ homeostasis. Gap junctions connect the cell cytoplasm, enabling the exchange of ions (Ca+ and K+), second messengers (AMPc, GMPc, IP3), several small metabolites (glucose) and ensuring electrical and metabolic coupling between the cells. The gap junctions are junctions with a selective permeability, formed by protein channels contained in the plasma membrane, and formed by connexin hexamers. Connexin hexamers might as well form hemichannel, linked the intracellular space to extracellular one.
Connexins are integral proteins of the plasma membrane, which are synthesized by practically every cell type, regardless of the position of a multicellular organism in the phylogenesis of the animal world. In vertebrates, occasional cells not producing connexins are adult striated muscle cells, spermatozoids and circulating blood cells. Unlike numerous membrane proteins, connexins have a short half-life (between 3 and 6 hours), are not glycosylated and do not have an enzymatic activity. At present, at least thirteen distinct connexins have been identified in mammals; corresponding, in humans, to 21 isoforms. In practice, various types of connexins can be present in a plurality of tissues, and most of the cells synthesize a plurality of connexins. Before reaching the cell membrane, the connexins assemble in groups of six molecules to form hollow tubular structures called connexons, which join the plasma membrane by means of Golgi vesicles. When cell contact is established, the connexons of a cell align end-to-end with those of the neighboring cell, establishing a continuous hydrophilic channel around 10 nm long. This junctional channel establishes direct contact between the cytoplasms of the two cells in contact, over the intercellular space.
Connexins are involved in a huge number of physiological processes, and several applications of connexin blocking agents (also called hereafter “connexin blocking agents” or “anti-connexin agents”) have been described.
For example, anti-connexin agents have been proposed for treating and/or preventing the following conditions:                cancers (WO2006/134494 and WO2006/049157),        some cardiovascular diseases (WO2006/134494),        wounds (WO2006/134494 and WO2009/097077),        pain (WO2009/148613),        migraines (Durham and Garrett, 2009),        epilepsy (Juszczak and Swiergiel, 2009),        neurological conditions (WO2006/134494) and neurodegenerative diseases (Takeuchi et al. 2011),        ischemia (Davidson et al, 2013),        drug-induced liver injury (Patel et al, 2012)        infectious diseases (WO2011/067607),        cytotoxicity induced by chemotherapeutic agents (Tong X. et al, 2013) and        inflammatory disorders (WO2006/134494).        
Furthermore, the present inventors previously described that anti-connexin agents are able to potentiate the therapeutic effects of psychotropic drugs (WO 2010/029131). In particular, they described that administration of anti-connexin agents such as meclofenamic acid (MFA) increases the therapeutic effects of various psychotropic molecules, enabling to reduce the active doses and thus the undesirable effects of these psychotropic molecules. These synergistic effects have been observed with a wide range of psychotropic molecules (clozapine, paroxetine, modafinil, diazepam, venlafaxine, escitalopram, bupropion and sertraline).
Identifying new anti-connexin agents is therefore of primary importance to highlight new therapeutic tools aiming to treat various diseases and disorders, in particular in combination with psychotropic drugs.
In this context, the inventors have now demonstrated that the well-known antiarrhythmic agent flecainide, has a broad anti-connexin activity. This is a very surprising result, since flecainide had been described so far to interfere with sodium channels, in particular on heart muscle cells, and these channels are not related with brain gap junctions. Moreover, flecainide had been shown not to influence junctional resistance of cardiac myocyte cell pairs (Daleau et al, 1998).